Abstract: FR-OR88
Longitudinal In Vivo Monitoring of Kidney Fibrosis Using Collagen I Luciferase Transgenic Mice
Session Information
- Pathology and Lab Medicine Advances
October 25, 2024 | Location: Room 2, Convention Center
Abstract Time: 05:30 PM - 05:40 PM
Category: Pathology and Lab Medicine
- 1800 Pathology and Lab Medicine
Authors
- Ma, Hualin, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
- Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Zou, Jun, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Interstitial fibrosis is closely associated with progression of chronic kidney disease. However, direct assessment of tissue-level fibrosis is limited by the invasiveness of biopsies. We investigated the potential of using collagen I-luciferase (Col(I)-Luc) transgenic mice to track dynamic changes in kidney fibrosis over time in vivo.
Methods
In Col(I)-Luc transgenic mice, the luciferase gene is driven by the collagen I promoter. We induced tubular injury in Col(I)-Luc mice by folic acid (FA) injection and treated a subgroup with dimethyloxaloylglycine (DMOG), an inhibitor of HIF-alpha prolyl hydroxylase. We also crossbred Col(I)-Luc mice with Nep25 mice, which express human CD25 under the nephrin promoter on podocytes. Podocyte injury can be induced by injection of LMB2 toxin that binds the receptor. We induced podocyte injury in Col(I)-Luc/Nep25 mice and treated a subgroup with angiotensin receptor blockers (ARB). In vivo bioluminescence imaging was performed at intervals.
Results
In vivo bioluminescence imaging captured luciferase activity in the kidneys, which correlated with kidney collagen I mRNA. The luciferase activity increased from baseline until week 6 in FA-injured mice, while the normal control had stable luciferase activity. Collagen I mRNA and protein were higher in FA vs control at week 6. DMOG reduced collagen I protein but not mRNA and luciferase activity. In the Nep25 model, low dose LMB2 induced increased proteinuria and luciferase activity at week 2, returning to normal at week 6. However, medium and high dose LMB2 markedly increased proteinuria and luciferase activity from week by week 6. ARB treatment in the high dose LMB2 mice numerically reduced luciferase activity reflecting decreased Col I mRNA but did not change the collagen I protein.
Conclusion
The Col(I)-Luc transgenic mouse model is an effective tool to longitudinally follow changes in collagen I mRNA in kidney disease. This model could be used to validate drug effects in preclinical studies. Utility will be greatest to monitor interventions that change Col I(mRNA), as the model design does not detect posttranslational changes in protein level.
Funding
- NIDDK Support